Tie2 Signaling Regulates Osteoclastogenesis and Osteolytic Bone Invasion of Breast Cancer
Tie2 Signaling Regulates Osteoclastogenesis and Osteolytic Bone Invasion of Breast Cancer
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DOI：
10.1158/0008-5472.can-09-1915
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发表时间：
2010-04-01
期刊：
影响因子：
11.2
通讯作者：
Lin, P. Charles
中科院分区：
文献类型：
--
作者：
Min, Yongfen;Ren, Xiubao;Lin, P. Charles
在大多数晚期乳腺癌患者中，乳腺骨转移是常见的。转移瘤通常是不可治愈的，并且与骨破坏和高发病率相关。了解转移性肿瘤细胞如何诱导骨破坏的潜在机制至关重要。我们以前报道，Tie 2，受体酪氨酸激酶，是显着增加，在人类乳腺癌组织与正常和良性乳腺肿瘤相比，调节肿瘤血管生成。在这项研究中，我们确定了一个新的功能Tie 2在破骨细胞和溶骨性乳腺癌骨浸润。Tie 2存在于造血干细胞/前体细胞中。在胚胎干细胞分化试验中，Tie 2基因缺失或使用可溶性Tie 2受体中和Tie 2功能损害破骨细胞生成。相反，Tie 2的缺失对成骨细胞生成没有影响。由于CD 11b骨髓细胞具有成为破骨细胞的潜力，并且Tie 2存在于这些细胞的特定群体中，因此我们分离了Tie 2（+）和Tie（2-）骨髓细胞。我们观察到Tie（2-）与Tie 2（+）CD 11b细胞相比，破骨细胞生成显著减少。一致地，体内Tie 2活性的中和显著抑制乳腺肿瘤模型中的溶骨性骨侵袭和肿瘤生长，这与破骨细胞和肿瘤血管生成的显著减少相关。总的来说，这些数据揭示了Tie 2信号在破骨细胞分化中的直接和新的作用。这些发现将Tie 2鉴定为不仅控制肿瘤血管生成而且控制乳腺癌中溶骨性骨转移的治疗靶标。Cancer Res; 70（7）; 2819-28. (C)2010年AACR。
Breast to bone metastasis is a common occurrence in the majority of patients with advanced breast cancer. The metastases are often incurable and are associated with bone destruction and high rates of morbidity. Understanding the underlying mechanisms of how metastatic tumor cells induce bone destruction is critically important. We previously reported that Tie2, a receptor tyrosine kinase, is significantly increased in human breast cancer tissues compared with normal and benign breast tumors and regulates tumor angiogenesis. In this study, we identify a new function of Tie2 in osteoclastogenesis and osteolytic bone invasion of breast cancer. Tie2 is present in hematopoietic stem/precursor cells. Genetic deletion of Tie2 or neutralization of Tie2 function using soluble Tie2 receptor impaired osteoclastogenesis in an embryonic stem cell differentiation assay. In contrast, deletion of Tie2 has no effect on osteoblastogenesis. As CD11b myeloid cells have the potential to become osteoclasts and Tie2 is present in a certain population of these cells, we isolated Tie2(+) and Tie(2-) myeloid cells. We observed a significant reduction of osteoclastogenesis in Tie(2-) compared with Tie2(+) CD11b cells. Consistently, neutralization of Tie2 activity in vivo significantly inhibited osteolytic bone invasion and tumor growth in a mammary tumor model, which correlated with a significant reduction of osteoclasts and tumor angiogenesis. Collectively, these data reveal a direct and novel role of Tie2 signaling in osteoclast differentiation. These findings identify Tie2 as a therapeutic target for controlling not only tumor angiogenesis but also osteolytic bone metastasis in breast cancer. Cancer Res; 70(7); 2819-28. (C) 2010 AACR.